The present invention relates to 2-amino-benzoic acid derivatives having general formula (I): ##STR3## wherein R is chlorine or trifluoromethyl; R' is of general formula ##STR4## wherein n=0 or 1 and m=4, 5, 6, 2-tetrahydropyranylmethyl, benzyloxymethyl, benzoyloxymethyl and 1(3H)-isobenzofuranone-3-yl; and to their non-toxic addition salts. Moreover, the present invention is concerned with a process for producing 2-amino-benzoic acid derivatives, in particular 2-amino-benzoic acid derivatives of the above general formula wherein R' is ##STR5##
The compounds of the above general formula, especially those compounds in which R' is ##STR6## are pharmacologically active having a remarkable analgesic and anti-inflammatory activity, and a low toxicity. Accordingly, these compounds, mixed with suitable carriers, can be administered orally in form of tablets, capsules, syrup, solution, etc., by injection or rectally wherein a daily dosage ranging from 200 to 1000 mg is used.
The compounds show an outstanding analgesic activity, especially upon oral application versus the brewer's yeast test in rat as described by Winter et al. (J. Pharm. Exp. Ther., 150(1), 165-171, 1965). Also these compounds have shown anti-inflammatory activity especially upon oral application versus the Carrageenin test in rats as described by Winter et al. (Proc. Soc. Exp. Biol. Med., 111, 544-547, 1962). The results for the analgesic evaluation are expressed as ED.sub.50 and those for the anti-inflammatory evaluation expressed as the activity rate observed on administering the compounds at a dose of 5 mg/kg. All these results are comparatively shown over acetylsalicylic acid, antrafenine, floctafenine and glafenine in table 1.
TABLE 1 __________________________________________________________________________ Compound Analgesic activity Antiinflammatory (as free base) R R' ED.sub.50 (mg/kg) activity (%) __________________________________________________________________________ Example 1 Cl ##STR7## 38 35,6 Example 2 CF.sub.3 ##STR8## 2,9 38,0 Example 3 Cl ##STR9## 67 23,1 Example 4 CF.sub.3 ##STR10## 3,0 23,2 Example 5 Cl ##STR11## 5,4 17,3 Example 6 CF.sub.3 ##STR12## 7,0 27,9 Example 7 Cl ##STR13## 18,5 5,1 Example 8 CF.sub.3 ##STR14## 14,7 26,2 Example 9 Cl ##STR15## 21,7 33,2 Example 11 Cl ##STR16## 13,3 21,2 Example 12 CF.sub.3 ##STR17## 6,6 28,8 Example 14 Cl ##STR18## 22 19,5 Example 15 CF.sub.3 ##STR19## 9,3 26,1 Example 16 Cl CH.sub.2OCH.sub.2Ph 6,3 27,7 Example 17 CF.sub.3 CH.sub.2OCH.sub.2Ph 64,5 30,5 Example 18 Cl CH.sub.2OCOPh 82,5 31,0 Example 19 CF.sub.3 CH.sub.2OCOPh 3,8 30,5 Example 20 Cl ##STR20## 71 26,2 Example 21 CF.sub.3 ##STR21## 26 38,4 Acetylsalycilic acid 73 23,2 Antrafenine 43 3,6 Floctafenine 2,2 21,6 Glafenine 26,5 25,6 __________________________________________________________________________
Moreover, the above compounds have shown a low toxicity which makes them useful in therapy. LD.sub.50 for some of the most active compounds are comparatively shown over glafenine in table 2. Evaluation was made according to the method by Reed-Muench as modified by Pizzi (Human & Biology, 22(3), 151-190, 1950) by oral administration to mice.
TABLE 2 ______________________________________ Compound LD.sub.50 (as free base) R R' (mg/kg) ______________________________________ Example 1 Cl ##STR22## 2000 Example 2 CF.sub.3 ##STR23## 630 Example 3 Cl ##STR24## &gt;2000 Example 4 CF.sub.3 ##STR25## 635 Example 16 Cl CH.sub.2OCH.sub.2Ph &gt;8000 Glafenine 2100 ______________________________________
Compounds of the present invention mixed with pharmaceutically acceptable carriers can be administered by oral application in form of tablets, capsules, syrup, solution, etc., by injection and by rectal application, at daily doses ranging from 200 to 1000 mg.
The compound (I) of the invention can be made in various ways.
(a) Reaction of a base compound having the general formula (II): ##STR26## with a compound having the general formula (III): X--R'. wherein R and R' is as outlined with formula I
R" is C.sub.1 -C.sub.4 -alkyl or hydrogen PA1 X is hydroxy or halogen
In those cases in which compound (II) has ester-like nature, i.e. R" is a C.sub.1 -C.sub.4 alkyl rest, preferable methyl, the reaction is carried out with compound (III) wherein X is OH; the reaction is properly catalyzed by sodium or sodium hydride and completed at boiling temperature in an aromatic solvent, such as toluene. This reaction is preferably applied when R' is ##STR27## wherein n and m are as defined above, or when R' is 2-tetrahydropyranylmethyl.
On the other hand, in those cases in which R" is hydrogen, the reaction is carried out with compound (III) wherein X is a halogen atom, selected between bromine and chlorine. This reaction is preferably applied when R' is benzyloxymethyl, benzoyloxymethyl and 1(3H)-isobenzofuranone-3-yl. Due to the insolubility of the acids (II, R"=H) in most of organic solvents, even polar aprotic solvents, as well as their inorganic salts, the use of organic salts, such as triethylamine, tri-n-butylamine or the like, is preferred which makes solubilization to be attained and consequently facilitating reaction to a great extent. The reaction then occurs under a highly-yielded step by using at room temperature hexamethylphosphorotriamide or N,N-dimethylformamide as solvent.
Compound (III), wherein X is OH and R' is ##STR28## wherein n is 0 and m is as defined above, are obtained according to the methods described by A. Lespagnol and J. Desprey (Bull. Soc. Chim. France, 3, 606-610, 1961). As for respective analogs with n=1, we have simplified their preparation by modifying the method by H. Najer et al. (Bull. Soc. Chim. France, 3, 355-359, 1958), since it has been found out that such intermediates are advantageously obtained by reacting commercially available 2-(2-chloroethoxy)ethanol and the corresponding cyclic amine, thus avoiding under pressure laboratory operations.
(b) Reaction of isatoic anhydride with intermediate alcohols of compound (IV), followed by subsequent alkylation with the corresponding 4-chloro-quinoleines (IV), leads to the compounds of general formula (I) in accordance with the following equation: ##STR29##
In the above diagram, R, n and m, for formulas (IV), (V) and (VI), are as defined above in connection with formula (I). The first reaction is suitably conducted in an aromatic solvent, for example, toluene, under the boiling point of same. The second reaction is suitably conducted in an acid aqueous solution, under the boiling point of same.
These reactions provide an industrially useful process since the isatoic anhydride is evidently a commercially available starting product.